Stable pharmaceutical compositions comprising a pyrimidine-sulfamide

ABSTRACT

The invention relates to stable pharmaceutical compositions comprising the compound of the below formula, or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/900,586 filed on Feb. 20, 2018, Continuation application of U.S.application Ser. No. 15/002,255 filed on Jan. 20, 2016, which is aContinuation application of U.S. application Ser. No. 13/736,699 filedon Jan. 8, 2013, which is a Continuation application of U.S. applicationSer. No. 12/388,142 filed on Feb. 18, 2009, which application is aContinuation-in-Part of U.S. application Ser. No. 12/066,448 filed onMar. 19, 2008, which is a U.S. filing under 35 U.S.C. 371 ofInternational Application No. PCT/IB2006/53210 filed on Sep. 11, 2006,which claims the benefit of PCT/EP2005/009775 filed on Sep. 12, 2005,the contents of each of which are incorporated herein by reference intheir entirety.

The present invention relates to stable pharmaceutical compositionscomprising propylsulfamic acid[5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts, solvates, hydrates ormorphological forms thereof, said compound being hereinafter referred toas the compound of formula I. The compound of formula I has thefollowing formula:

The compound of formula I is an endothelin receptor inhibitor and usefulas endothelin receptor antagonist. The compound of formula I and thepreparation thereof is disclosed in WO 02/053557.

Within the context of this disclosure, any reference to the compound offormula I is to be understood as referring also to the pharmaceuticallyacceptable salts or solvates, including hydrates, of the compound offormula I, as well as to the morphological forms thereof, if notindicated otherwise and where appropriate and expedient.

The present compound of formula I is currently being evaluated inclinical trials, thus a stable formulation had to be developed. Thepresent invention therefore relates to stable pharmaceuticalcompositions comprising the compound propylsulfamic acid[5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide,or pharmaceutically acceptable salts, solvates, hydrates ormorphological forms thereof.

A stable pharmaceutical composition according to this invention willcomprise:

-   -   a) the compound of formula I having the formula shown hereafter,        or a pharmaceutically acceptable salt, solvate, hydrate or        morphological form thereof,

-   -   b) a filler,    -   c) a disintegrant,    -   d) a surfactant,    -   e) a lubricant.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the dissolution profile for the compositions of Examples16-20.

FIG. 2 shows the process for the preparation of a pharmaceuticalcomposition in the form of capsules according to the present invention.

FIG. 3 shows the process for the preparation of a pharmaceuticalcomposition in the form of tablets according to the present invention.

FIG. 4 shows a process summary for the preparation of the pharmaceuticalcomposition of Examples 1-15.

FIG. 5 shows a wet granulation process summary for the preparation ofthe pharmaceutical compositions of Reference Examples RE1 to RE4 and ofExamples 16 to 33, 40, 41, and 43.

FIG. 6 shows a direct compression process summary for the preparation ofthe pharmaceutical compositions of Examples 34-35.

According to a preferred embodiment of this invention, thepharmaceutical composition will be in the form of a tablet.

According to another preferred embodiment of this invention, thepharmaceutical composition will be in the form of a capsule.

Stable pharmaceutical compositions according to this invention willpreferably be such that the filler is selected from one or more of thefollowing: lactose, maize starch, pregelatinized starch, dibasic calciumphosphate dihydrate (CaHPO₄.2H₂O), microcrystalline cellulose,maltodextrin and mannitol; the disintegrant is selected from one or moreof the following: croscarmellose sodium, sodium starch glycolate,calcium carboxymethylcellulose, sodium carboxymethylcellulose,cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, alginic acid,sodium alginate, pregelatinized starch, guar gum, clays and ion exchangeresins; the surfactant is selected from the following: sodium laurylsulphate, polysorbates, polyethylene polyoxypropylene polymers,polyoxylethylene stearates, dioctyl sodium sulfosuccinate,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene C₁₋₄-alkylethers, sucrose monoesters and lanolin esters and ethers; and thelubricant is selected from the following: magnesium, aluminium orcalcium stearate, stearic acid, sodium stearyl fumarate, talc, sodiumbenzoate, glyceryl mono fatty acid, polyethylene glycol, hydrogenatedcotton seed oil, castor seed oil and sucrose esters.

In particular, a stable pharmaceutical composition according to thisinvention can comprise:

-   -   a) the compound of formula I as defined above, or a        pharmaceutically acceptable salt, solvate, hydrate or        morphological form thereof,    -   b) one or more excipients selected from the group consisting of        lactose, maize starch, pregelatinised starch, calcium hydrogen        phosphate and microcrystalline cellulose,    -   c) polyvinylpyrrolidone,    -   d) sodium starch glycolate,    -   e) a surfactant, and    -   f) a lubricant.

More particularly, a stable pharmaceutical composition according to thisinvention can comprise:

-   -   a) the compound of formula I as defined above, or a        pharmaceutically acceptable salt, solvate, hydrate or        morphological form thereof, in a total amount of up to 50% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 1 to 50%, notably from 5 to        30% and in particular from 10 to 20% in weight based on the        total weight of the pharmaceutical composition),    -   b) one or more excipients selected from the group consisting of        lactose, maize starch, pregelatinised starch, calcium hydrogen        phosphate and microcrystalline cellulose, in a total amount of        10 to 95% in weight based on the total weight of the        pharmaceutical composition (e.g. in an amount from 30 to 90%,        notably from 50 to 80% and in particular from 60 to 75% in        weight based on the total weight of the pharmaceutical        composition),    -   c) polyvinylpyrrolidone, in a total amount of up to 20% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 0.5 to 10%, notably from 1        to 5% and in particular from 2 to 4% in weight based on the        total weight of the pharmaceutical composition),    -   d) sodium starch glycolate, in a total amount of up to 30% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 0.5 to 20%, notably from 1        to 10% and in particular from 2 to 6% in weight based on the        total weight of the pharmaceutical composition),    -   e) a surfactant, in a total amount of up to 7% in weight based        on the total weight of the pharmaceutical composition (e.g. in        an amount from 0.01 to 5%, notably from 0.05 to 1% and in        particular from 0.1 to 0.5% in weight based on the total weight        of the pharmaceutical composition), and    -   f) a lubricant, in a total amount of up to 10% in weight based        on the total weight of the pharmaceutical composition (e.g. in        an amount from 0.05 to 5%, notably from 0.1 to 2% and in        particular from 0.25 to 1.5% in weight based on the total weight        of the pharmaceutical composition).

For example, a stable pharmaceutical composition according to thisinvention can comprise:

-   -   a) the compound of formula I as defined above, or a        pharmaceutically acceptable salt, solvate, hydrate or        morphological form thereof, in a total amount of up to 50% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 1 to 50%, notably from 5 to        30% and in particular from 10 to 20% in weight based on the        total weight of the pharmaceutical composition),    -   b) lactose or lactose monohydrate in a total amount of 10 to 75%        in weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 30 to 70%, notably from 45        to 65% and in particular from 52 to 60% in weight based on the        total weight of the pharmaceutical composition)    -   c) microcrystalline cellulose, in a total amount of 0 to 20% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 1 to 10%, notably from 2 to        8% and in particular from 4 to 6% in weight based on the total        weight of the pharmaceutical composition),    -   d) polyvinylpyrrolidone, in a total amount of up to 20% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 0.5 to 10%, notably from 1        to 5% and in particular from 2 to 4% in weight based on the        total weight of the pharmaceutical composition),    -   e) sodium starch glycolate, in a total amount of up to 30% in        weight based on the total weight of the pharmaceutical        composition (e.g. in an amount from 0.5 to 20%, notably from 1        to 10% and in particular from 2 to 6% in weight based on the        total weight of the pharmaceutical composition),    -   f) a surfactant, in a total amount of up to 7% in weight based        on the total weight of the pharmaceutical composition (e.g. in        an amount from 0.01 to 5%, notably from 0.05 to 1% and in        particular from 0.1 to 0.5% in weight based on the total weight        of the pharmaceutical composition), and    -   g) a lubricant, in a total amount of up to 10% in weight based        on the total weight of the pharmaceutical composition (e.g. in        an amount from 0.05 to 5%, notably from 0.1 to 2% and in        particular from 0.25 to 1.5% in weight based on the total weight        of the pharmaceutical composition).

A pharmaceutical composition according to this invention can notablycomprise:

-   -   a) the compound of the formula I as defined above, or a        pharmaceutically acceptable salt, solvate, hydrate or        morphological form thereof,    -   b) lactose or lactose monohydrate,    -   c) microcrystalline cellulose,    -   d) polyvinylpyrrolidone,    -   e) sodium starch glycolate,    -   f) a surfactant, and    -   g) a lubricant.

According to a preferred embodiment of the compositions mentioned above,the surfactant is a polysorbate.

According to another preferred embodiment of the compositions mentionedabove, the lubricant is magnesium stearate.

Optionally, the stable pharmaceutical composition of this invention mayalso contain a glidant. The present invention therefore further providesstable pharmaceutical compositions, comprising:

-   -   a) the compound of formula I, or a pharmaceutically acceptable        salt, solvate, hydrate or morphological form thereof,    -   b) a filler,    -   c) a disintegrant,    -   d) a surfactant,    -   e) a glidant, and    -   f) a lubricant.

Fillers according to the invention include but are not restricted to oneor more of the following: lactose, maize starch, pregelatinized starch,dibasic calcium phosphate dihydrate (CaHPO₄.2H₂O), microcrystallinecellulose, maltodextrin and mannitol. Preferably, lactose withmicrocrystalline cellulose, lactose with maize starch, pregelatinizedstarch with microcrystalline cellulose, or dibasic calcium phosphatedihydrate with microcrystalline cellulose are used. Also preferred islactose monohydrate (e.g. Pharmatose® 200 Mesh) with microcrystallinecellulose (e.g. Avicel® PH101).

Disintegrants according to the invention include but are not restrictedto one or more of the following: croscarmellose sodium, sodium starchglycolate, calcium carboxymethylcellulose (CMC-Ca), sodiumcarboxymethylcellulose CMC-Na, cross-linked polyvinylpyrrolidone (e.g.Crospovidone (PVP XL; Polyplasdone, commercially available from the ISPcompany or Kollidon® XL from BASF)), polyvinylpyrrolidone (PVP), alginicacid, sodium alginate, pregelatinized starch, guar gum, clays and ionexchange resins. Preferably, sodium starch glycolate is used asdisintegrant, or a combination of sodium starch glycolate and PVP.

Surfactant according to the invention include but are not restricted toone or more of the following: sodium lauryl sulphate, polysorbates(commercially available as Tween®), polyethylene polyoxypropylenepolymers (Pluronic F65), polyoxylethylene stearates (MYRJ), dioctylsodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters(commercial available from Nikko Chemicals), polyoxyethylene C₁₋₄-alkylethers, sucrose monoesters and lanolin esters and ethers. Preferably,sodium lauryl sulphate is used as surfactant.

A polysorbate included in a composition according to the presentinvention will have a mean polymerisation degree of from 20 to 100monomer units (preferably about 80), and may for example be polysorbate80. Preferably also, the polysorbate should be vegetable-derived.

Glidants according to the invention include but are not restricted toone or more of the following: silica; colloidal silicon dioxide, e.g.colloidal silica anhydrous (e.g. Aerosil® 200), magnesium trisilicate,powdered cellulose, starch and talc. Preferably, colloidal siliconedioxide is used.

Lubricants according to the invention include but are not restricted toone or more of the following: Mg-, Al- or Ca-stearate, stearic acid,sodium stearyl fumarate, talc, sodium benzoate, a glyceryl mono fattyacid, e.g. having a molecular weight of from 200 to 800 Daltons (e.g.glyceryl monostearate (e.g. from Danisco, UK)), glyceryl dibehenate(e.g. CompritolAT0888™, Gattefosse France), glyceryl palmito-stearicester (e.g. Precirol™, Gattefosse France), polyethylene glycol (PEG,BASF), hydrogenated cotton seed oil (Lubitab, Edward Mendell Co Inc.),castor seed oil (Cutina HR, Henkel) and sucrose esters (Surfhope SE,Mitsubishi-Kagaku Foods Co.). Preferably, magnesium stearate is used.

It will be appreciated that any given excipient may serve more than onefunction e.g. as filler, disintegrant, surfactant, glidant, and/orlubricant.

Optionally, the stable pharmaceutical composition of this invention(whether containing a glidant or not) may also contain tartaric acid.

Lactose as available from commercial suppliers is used for the presentinvention, preferably Lactose-monohydrate (such as Pharmatose® 200M fromDMV International) is used for the present invention.

Maize starch, as available from commercial suppliers is used for thepresent invention, preferably maize starch from Roquette.

Pregelatinised starch as available from commercial suppliers is used forthe present invention, preferably Starch 1500 (from Colorcon).

Dibasic calcium phosphate dihydrate as available from commercialsuppliers is used for the present invention, preferably dibasic calciumphosphate dihydrate in an unmilled form, such as Calipharm A or A-Tab.

Microcrystalline cellulose as available from commercial suppliers isused for the present invention, preferably Avicel PH101 from FMCinternational.

Polyvinylpyrrolidone (PVP), as available from commercial suppliers isused for the present invention, preferably polyvinylpyrrolidone fromBASF.

Sodium starch glycolate, as available from commercial suppliers is usedfor the present invention, preferably sodium starch glycolate fromRoquette.

Sodium lauryl sulphate, as available from commercial suppliers is usedfor the present invention, preferably sodium lauryl sulphate from Ellis& Everard.

Colloidal silicon dioxide, as available from commercial suppliers isused for the present invention, preferably Aerosil from Degussa AG.

Magnesium stearate, as available from commercial suppliers is used forthe present invention, preferably Magnesium stearate from Peter Greven.

The term “C₁₋₄-alkyl”, alone or in combination with other groups, meansa straight-chain or branched-chain alkyl group with 1 to 4 carbon atoms.Examples of straight-chain and branched C₁-C₄ alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl.

The term “about” placed before a numerical value “X” refers in thecurrent application to an interval extending from X minus 10% of X to Xplus 10% of X, and preferably to an interval extending from X minus 5%of X to X plus 5% of X.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrochloric orhydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formicacid, acetic acid, maleic acid, tartaric acid, benzoic acid,methanesulfonic acid, p-toluenesulfonic acid, and the like that are nontoxic to living organisms or in case the compound of formula (I) isacidic in nature with an inorganic base like an alkali or earth alkalibase, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide andthe like.

The expression ww % refers to a percentage by weight compared to thetotal weight of the composition considered.

In a preferred embodiment of the invention the pharmaceuticalcompositions comprise:

a filler which is selected from one or more of the following: lactose,maize starch, pregelatinized starch, dibasic calcium phosphate dihydrate(CaHPO₄.2H₂O) and microcrystalline cellulose, maltodextrin and mannitol;a disintegrant which is selected from one or more of the following:croscarmellose sodium, sodium starch glycolate, CMC-Ca, CMC-Na,cross-linked PVP, PVP, alginic acid, sodium alginate, pregelatinizedstarch, guar gum, clays and ion exchange resins; a surfactant which isselected from the following: sodium lauryl sulphate, polysorbates,polyethylene polyoxypropylene polymers, polyoxylethylene stearates anddioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acidesters, polyoxyethylene C₁₋₄-alkyl ethers, sucrose monoesters andlanolin esters and ethers; a glidant which is selected from thefollowing: silicon dioxide, colloidal silica, magnesium trisilicate,powdered cellulose, starch and talc; a lubricant which is selected fromthe following: Mg-, Al- or Ca-stearate, stearic acid, sodium stearylfumarate, talc, sodium benzoate, glyceryl mono fatty acid, polyethyleneglycol, hydrogenated cotton seed oil, castor seed oil and sucroseesters.

In another preferred embodiment of the invention the pharmaceuticalcompositions comprise a) a mixture of at least one or more of thefollowing excipients selected from lactose, maize starch, pregelatinisedstarch, calcium hydrogen phosphate and microcrystalline cellulose,

-   -   b) polyvinylpyrrolidone,    -   c) sodium starch glycolate,    -   d) sodium lauryl sulphate,    -   e) colloidal silicon dioxide, and    -   f) magnesium stearate.

In a further preferred embodiment of the invention, the pharmaceuticalcomposition, comprise

-   -   a) a mixture of at least one or more of the following excipients        selected from Lactose, Maize starch, Starch 1500, Calipharm A        and Avicel PH101,    -   b) polyvinylpyrrolidone,    -   c) sodium starch glycolate,    -   d) sodium lauryl sulphate,    -   e) Aerosil, and    -   f) magnesium stearate.

In another preferred embodiment of the invention the pharmaceuticalcompositions comprise

-   -   a) the compound of formula I, or pharmaceutically acceptable        salts, solvates, hydrates or morphological forms thereof, in a        total amount of up to 50% in weight based on the total weight of        the pharmaceutical composition,    -   b) a mixture of at least one or more of a filler in a total        amount of 10-95% in weight based on the total weight of the        pharmaceutical composition,    -   c) polyvinylpyrrolidone in a total amount of up to 20% in weight        based on the total weight of the pharmaceutical composition,    -   d) sodium starch glycolate in a total amount of up to 30% in        weight based on the total weight of the pharmaceutical        composition,    -   e) a surfactant in a total amount of up to 7% in weight based on        the total weight of the pharmaceutical composition,    -   f) a glidant in a total amount of up to 5% in weight based on        the total weight of the pharmaceutical composition, and    -   g) a lubricant in a total amount of up to 10% in weight based on        the total weight of the pharmaceutical composition,        whereby the total ww % of the pharmaceutical composition is 100.

In a further preferred embodiment of the invention, the pharmaceuticalcomposition, comprise

-   -   a) the compound of formula I, or pharmaceutically acceptable        salts, solvates, hydrates or morphological forms thereof, in a        total amount of up to 50% in weight based on the total weight of        the pharmaceutical composition,    -   b) a mixture of at least one or more of a filler in a total        amount of 30-85% in weight based on the total weight of the        pharmaceutical composition,    -   c) polyvinylpyrrolidone in a range of a total amount of 2 to 10%        in weight based on the total weight of the pharmaceutical        composition,    -   d) sodium starch glycolate in a total amount of up to 10% in        weight based on the total weight of the pharmaceutical        composition,    -   e) a surfactant in a total amount of up to 3% in weight based on        the total weight of the pharmaceutical composition,    -   f) a glidant in a total amount of up to 2.5% in weight based on        the total weight of the pharmaceutical composition, and    -   g) a lubricant in a total amount of up to 7% in weight based on        the total weight of the pharmaceutical composition,        whereby the total ww % of the pharmaceutical composition is 100.

In another preferred embodiment of the invention the pharmaceuticalcompositions comprise

-   -   a) the compound of formula I, or pharmaceutically acceptable        salts, solvates, hydrates or morphological forms thereof, in a        total amount of up to 50% in weight based on the total weight of        the pharmaceutical composition,    -   b) a mixture of at least one or more of a filler in a total        amount of 30-85% in weight based on the total weight of the        pharmaceutical composition,    -   c) polyvinylpyrrolidone in a range of a total amount of 2 to 5%        in weight based on the total weight of the pharmaceutical        composition,    -   d) sodium starch glycolate in a total amount of up to 5% in        weight based on the total weight of the pharmaceutical        composition,    -   e) a surfactant in a total amount of up to 3% in weight based on        the total weight of the pharmaceutical composition,    -   f) a glidant in a total amount of up to 1% in weight based on        the total weight of the pharmaceutical composition, and    -   g) a lubricant in a total amount of up to 3% in weight based on        the total weight of the pharmaceutical composition,        whereby the total ww % of the pharmaceutical composition is 100.

The pharmaceutical compositions or pharmaceutically acceptable salts,solvates, hydrates or morphological forms thereof, according to theinvention, may be used as a medicament.

The pharmaceutical compositions or pharmaceutically acceptable salts,solvates, hydrates or morphological forms thereof, according to theinvention, may be used for the preparation of a medicament, for use inthe treatment of pulmonary arterial hypertension (PAH).

Reference is made to the extensive literature on the subject for theseand other pharmaceutically acceptable excipients and proceduresmentioned herein, see in particular Handbook of PharmaceuticalExcipients, Third Edition, edited by Arthur H. Kibbe, AmericanPharmaceutical Association, Washington, USA and Pharmaceutical Press,London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik andangrenzende Gebiete edited by H. P. Fiedler, 4th Edition, Edito Cantor,Aulendorf and earlier editions.

According to the present invention, the amount of compound of formula I,or pharmaceutically acceptable salts, solvates, hydrates ormorphological forms thereof, may be a total amount of up to 90% inweight based on the total weight of the pharmaceutical composition.Preferably, the amount of compound of formula I, or pharmaceuticallyacceptable salts, solvates, hydrates or morphological forms thereof, maybe a total amount of up to 50% in weight based on the total weight ofthe pharmaceutical composition. More preferably, the amount of compoundof formula I, or pharmaceutically acceptable salts, solvates, hydratesor morphological forms thereof, will be from 1 to 50%, notably from 5 to30% and in particular from 10 to 20% in weight based on the total weightof the pharmaceutical composition.

According to the present invention, the amount of filler may vary withina range of 10 to 95%, in particular 30 to 85% and more particularly 30to 50% in weight based on the total weight of the pharmaceuticalcomposition.

The amount of disintegrant may vary from 1 to 20%, preferably from 2 to10% (e.g. from 3 to 8%) and notably from 2 to 5% in weight based on thetotal weight of the pharmaceutical composition. For example, thecomposition may contain 2 to 4% (e.g. 3%) disintegrant in weight basedon the total weight of the pharmaceutical composition.

The amount of surfactant may vary from 0.01 to 7%, preferably from 0.1to 3% and in particular from 0.1 to 1% in weight based on the totalweight of the pharmaceutical composition.

The amount of glidant, when present in composition, may vary withinranges of from 0.1 to 5%, in particular 0.1 to 2.5%, especially 0.5 to1.0% in weight based on the total weight of the pharmaceuticalcomposition.

The amount of lubricant may vary from 0.05 to 10%, preferably from 0.05to 7%, most preferably from 0.1 to 3.0% and notably between 0.1 and 1%in weight based on the total weight of the pharmaceutical composition.

The amount of tartaric acid, when present in the composition, may varyfrom 0.1 to 10%, preferably from 1 to 10%, and most preferably from 4 to6% in weight based on the total weight of the pharmaceuticalcomposition.

The absolute amounts of each pharmaceutically acceptable excipient andthe amounts relative to other pharmaceutically acceptable excipients aredependent on the desired properties of the tablet and can be chosen byroutine experimentation.

The total weight percent of the pharmaceutical composition is 100.

A pharmaceutical composition according to the invention is considered“stable”, if during a certain period of time 70%, preferably 80% andmost preferably 95% of the initial content of compound of formula I, orpharmaceutically acceptable salt, solvate, hydrate or morphological formthereof, is maintained over said period of time.

The stability of the pharmaceutical composition may be tested inconventional manner, e.g. by measurement of compound of formula I andits degradation products, dissolution, friability, disintegration time,appearance and/or microscopy, e.g. after storage at 25° C. and 60%relative humidity, and/or storage at 40° C. and 75% relative humidityfor defined periods of time.

An example of a dissolution test procedure is given in the experimentalpart following the Examples.

Preferably, the solid compositions of this invention will be stable forat least 6 or 12 months when kept at a temperature of 5 to 50° C. Morepreferably, they will be stable for at least 6 or 12 months when kept ata temperature of 15 to 45 C. Most preferred, they will be stable for atleast 6 or 12 months when kept at a temperature of 25 to 40° C.

In a more preferred embodiment, the pharmaceutical compositions arestable over a certain period of time such as 1 year, and preferably 2years. More preferably, the pharmaceutical compositions are stable for 3years.

The content of compound of formula I and its degradation products in thecapsules or tablets was evaluated via HPLC.

The pharmaceutical composition may be formulated as capsule and tablet.For example a batch size of 1625 g (6500 capsules) of 1 mg dosagestrength may be prepared as follows:

Percentage Unit For 6500 Material Formula Dose capsules (Chemical name)Function (% w/w) (mg) (g) Intra- Compound of formula I Active 0.40 1.006.5 granular Pregelatinized maize starch, EP/BP/NF Diluent 73.30 183.251191.125 Microcrystalline cellulose, EP Diluent/disintegrant 10.00 25.00162.500 Sodium starch glycollate, EP Disintegrant 2.00 5.00 32.500Sodium lauryl sulphate, EP/NF Surfactant 1.00 2.50 16.250 Extra-Microcrystalline cellulose, EP Diluent/disintegrant 10.00 25.00 162.500granular Sodium starch glycollate, EP Disintegrant 2.00 5.00 32.500Colloidal silicone dioxide, EP/NF Glidant 0.30 0.75 4.875 Magnesiumstearate, EP/BP Lubricant 1.00 2.50 16.250 Total 100.000 250.00 1625.00

The intragranular materials were pre-mixed in a high shear mixer e.g. aDiosna, (6 L bowl) for 5 minutes. About 731-893 g of water at a rate of65 g/minute was added to the intra-granular materials whilst mixinguntil suitable granules were formed. The intra-granular materials werefurther mixed for 2 minutes. They were then dried in a fluid bed dryerwith an inlet air temperature of 60° C. until the loss on drying of thegranules were 6-9% w/w. The granules were then passed through a co-millfitted with a 813 μm screen. All the extra-granular materials exceptmagnesium stearate were passed through a 1000 inn screen and were mixedwith the granules for 25 minutes at 25 rpm in a 10 L Pharmatech doublecone shell mixer. The magnesium stearate was screened through a 500 μmsieve and added to the rest of the powder mixture in the mixer and mixedfor a further 3 minutes.

The powder was then filled in a size “0”, white-opaque hard gelatinecapsules.

In one aspect of the invention one or more lubricants may be sprayed onthe material contacting surfaces of pressing tools, e.g. punches and/ordies, of the tabletting machine before compression.

The capsules may vary in size e.g. size 1 to “00”.

According to the invention, tablets may also be produced. The tabletsmay vary in shape and be, for example, round, oval, oblong, cylindrical,clover-shaped or any other suitable shape.

In an embodiment of the invention the tablets obtained are clover shapedor round. The edges of the tablets may be beveled or rounded. In anotherembodiment, the tablets are clover shaped with beveled edges. Thetablets according to the invention may be scored or engraved.

The tablet according to the invention may also be clover-shaped,quadrisected with beveled edges. It may have a diameter ranging between5 and 15 mm (for example a diameter of 5 to 8 mm such as a diameter of 6mm), notably a diameter ranging between 8 and 15 mm, and in particular adiameter ranging between 9 and 11 mm Its thickness (before coating, if acoating pellicle is applied on the tablet) is ranging from 2.5 to 4.5mm, preferably between 2.9 and 3.9 mm.

The capsules and tablets of the invention may be colored and/or markedso as to impart an individual appearance and to make them instantlyrecognizable. The use of dyes can serve to enhance the appearance aswell as to identify the tablets. Dyes suitable for use in pharmacytypically include carotinoids, iron oxides or chlorophyll. The tabletsof the invention may be marked using an imprint code.

The capsules and tablets of the present invention are useful for thetreatment of PAH and exhibit a good pharmacokinetic profile.

Procedures which may be used may be conventional or known in the art orbased on such procedures e.g. those described in L. Lachman et al., TheTheory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker etal., Pharmazeutische Technologie, Thieme, 1991; Hagers Handbuch derpharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington'sPharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or latereditions.

The process for the preparation of a pharmaceutical composition in theform of capsules according to the present invention can be carried outaccording to the process flow chart shown in FIG. 2.

The drying step can notably be carried out using a fluid bed dryer.

When the pharmaceutical composition to be prepared is in the form oftablets, the preparation process according to the present invention canbe carried out according to the process flow chart shown in FIG. 3.

Two variants of this process may be carried out, one involving wetgranulation (i.e. the process as shown in the flow chart above whereinsome water is added to the intra-granular materials, said water beingremoved by the drying step), and the other involving direct compression(i.e. the process as shown in the flow chart above less the drying step,said drying step being superfluous since no water is added to theintra-granular materials).

According to a preferred variant of the process, the tablets obtained bythe preparation process set out previously are coated by a protectivepellicle. Said protective pellicle will notably prevent direct contactof the tablet with moisture; they may also ease imprints in the tablet.

According to this invention, the amount of coating material by weightwill be from 2 to 8%, preferably from 3 to 7% and more preferably from 4to 6% of the weight of the tablet before its coating.

The coating material making said protective pellicle will include a lowwater vapour permeability polymer (such as a polyvinyl alcohol (e.g.Opadry® AMB) or dimethylaminoethyl methacrylate (e.g. EUDRAGIT® E PO)).The coating material can further include a plasticizing agent (e.g.propylene glycol, triacetyne, dibutyl phthalate or dibutyl sebacate), asurfactant (e.g. sodium lauryl sulphate or a polysorbate such as Tween)and/or a lubricant/glidant (e.g. stearic acid, magnesium or calciumstearate or talc). Moreover, the coating material can also include apigment (e.g. iron(II) oxide, iron(III) oxide or titanium oxide) to givethe tablet a coloured aspect.

The following non-limitative examples illustrate the invention.

EXAMPLES

The pharmaceutical compositions of Examples 1-15 were prepared accordingto a process summarized by the flow chart shown in FIG. 4.

The pharmaceutical compositions of Reference Examples RE1 to RE4 and ofExamples 16 to 33, 40, 41 and 43 were prepared by following a wetgranulation process summarized by the flow chart shown in FIG. 5.

Eventually, the pharmaceutical compositions of Examples 34-35 wereprepared by following a direct compression process summarized by theflow chart shown in FIG. 6.

(Note that in the flow charts above, RPM means rotations per minute)

Regarding the coating of tablets with Opadry® AMB, the methodologydetailed hereafter (later referred to as “general tablet coatingmethodology with Opadry® AMB”) was used.

The coating solution for the Opadry® AMB coated tablets was obtained bypreparing a 20% w/w dispersion of the Opadry® AMB (a fine white powder)in purified water in a stainless steel vessel at room temperature. Thedispersion was stirred using a Heidolph stirrer equipped with astainless steel paddle for 45 minutes before use and throughout thecoating process. The coating pan was allowed to equilibrate to the setpoint temperature (60° C.) prior to charging with tablets. The tabletswere equilibrated in the drying pan for 10 minutes prior to coating. Thesame temperature and airflow was used for the heating, coating anddrying phases.

The parameters used for coating the tablets containing the compound offormula (I) are as follows:

Coating Pan Accelacota 24” equipped with a Manesty Flowtab unit. InletTemperature 60° C. Exhaust Temperature 40° C. Drum Speed 12-14 RPM SprayRate 10 g/min increasing to 15 g/min after 60 min spraying Fluid nozzle(mm) 1.2 mm Spray gun Manesty MK-2 Atomising Air Pressure 50 psi FanWidth Air Pressure 50 psi Weight of dummy tablets used to 7000 bulk outthe tablet bed (g) Weight of active tablets (g) 300 ~No. of activetablets 4300 Total weight of tablet bed (g) 7300

The airflow in the coating pan was not measured at the time of coatingbut has subsequently been measured and was found to be approximately 250m³ per hour. The film coating took between 110 and 120 minutes tocomplete (coating was stopped when 1460 g of the solution had beensprayed). The tablets were dried for 10 min in the pan after coating.

Regarding the coating of tablets with EUDRAGIT® E PO, the methodologydetailed hereafter (later referred to as “general tablet coatingmethodology with EUDRAGIT® E PO”) was used.

The coating trail was performed in a Lödige LHC 25. The spray gun typewas an airborne spray gun Schlick 970/7-1 S75 with a nozzle diameter of1.2 mm. As delivery system for the spraying suspension a Verder CD 70peristaltic pump and a silicone tube with 2 mm internal diameter wereused.

The coating suspension for the EUDRAGIT® E PO coated tablets wasobtained as follows. Water was given in a container, the relevantquantity of sodium lauryl sulphate was added and the mixture washomogenised for 5 min using an ULTRA Turrax. Afterwards the relevantquantity of stearic acid was added in small portions and homogenised for5-10 min. After this homogenisation period, EUDRAGIT® E PO was addedslowly in small portions and homogenised for 30 min. Then the relevantquantity of magnesium stearate was prepared as 15% suspension in waterby means of an ULTRA Turrax and homogenised. The magnesium stearatesuspension was given to the EUDRAGIT® E PO solution. The final coatingsuspension was stirred continuously with conventional propeller stirrerduring the process.

Reference Examples RE1 and RE2

Batch sizes: 500 g each

Compound of formula I tablets (250 mg) Reference Example ReferenceExample RE1 RE2 Percentage Percentage MATERIAL Formula Unit Dose FormulaUnit Dose (CHEMICAL NAME) (% w/w) (mg) (% w/w) (mg) Intra-granularCompound of formula I 0.40 1.00 0.40 1.00 Pharmatose 200M 76.59 191.47575.60 189.00 Avicel PH101 5.00 12.50 5.00 12.50 Povidone K30 3.00 7.503.00 7.50 Sodium starch glycolate 2.00 5.00 2.00 5.00 Sodium laurylsulphate 0.01 0.025 1.00 2.50 Water qs qs qs qs Extra-granular AvicelPH101 10.00 25.00 10.00 25.00 Sodium starch glycolate 2.00 5.00 2.005.00 Magnesium stearate 1.00 2.50 1.00 2.50 Total 100.00 250.00 100.00250.00

Reference Examples RE3 and RE4

Batch sizes: 500 g each

Compound of formula I tablets (250 mg) Reference Example ReferenceExample RE3 RE4 Percentage Percentage MATERIAL Formula Unit Dose FormulaUnit Dose (CHEMICAL NAME) (% w/w) (mg) (% w/w) (mg) Intra-granularCompound of formula I 0.40 1.00 0.40 1.00 Pharmatose 200M 76.60 191.5075.55 191.375 Avicel PH101 5.00 12.50 5.00 12.50 Povidone K30 3.00 7.503.00 7.50 Sodium starch glycolate 2.00 5.00 2.00 5.00 Tween 80V 0 0 0.050.125 Water qs qs qs qs Extra-granular Avicel PH101 10.00 25.00 10.0025.00 Sodium starch glycolate 2.00 5.00 2.00 5.00 Magnesium stearate1.00 2.50 1.00 2.50 Total 100.00 250.00 100.00 250.00

Example 1

Batch size: 20 g

Materials % w/w Compound of formula I 40.0 Pharmatose DCL11 28.7 Starch1500 25.0 Sodium starch glycolate 4.0 Sodium lauryl sulphate 1.0Colloidal silicon dioxide 0.3 Magnesium stearate 1.0 Total 100.0

Examples 2 and 3

Batch size: 625 g

Materials Example 2 Example 3 Compound of formula I 0.08 0.08 PharmatoseDCL11 68.62 — Starch 1500 — 93.62 Avicel PH101 25.00 — Sodium starchglycolate 4.00 4.00 Sodium lauryl sulphate 1.00 1.00 Aerosil 200 0.300.30 Magnesium stearate 1.00 1.00 100 100

Examples 4-11

Intra-granular materials Extra-granular materials % w/ % w/w % w/w % w/wCompound % w/w % w/w % w/w % w/w % w/w % w/w sodium sodium % w/w sodium% w/w % w/w of Pharmatose ® Maize Starch Calipharm Avicel Polyvinyl-starch lauryl Avicel starch Aerosil Magnesium formula I 200M starch 1500A PH101 pyrrolidone glycollate sulphate PH101 glycollate 200 stearate0.08 70.62 — — — 10.00 3.00 2.00 1.00 10.00 2.00 0.30 1.00 0.08 — —73.62 — 10.00 — 2.00 1.00 10.00 2.00 0.30 1.00 40.00  30.70 — — — 10.003.00 2.00 1.00 10.00 2.00 0.30 1.00 40.00  — — 33.70 — 10.00 — 2.00 1.0010.00 2.00 0.30 1.00 0.40 70.30 — — — 10.00 3.00 2.00 1.00 10.00 2.000.30 1.00 0.40 — — 73.30 — 10.00 — 2.00 1.00 10.00 2.00 0.30 1.00 0.0870.62 20.00 — — — 3.00 2.00 1.00 — 2.00 0.30 1.00 0.08 — — — 70.62 10.003.00 2.00 1.00 10.00 2.00 0.30 1.00

Example 12

Compound of formula I Capsules 0.2 mg Typical Percentage Unit BatchMaterial Formula Dose Quantity (Chemical name) Function (% w/w) (mg) (g)Intra- Compound of Active 0.08 0.20 0.600 granular formula IPregelatinized Diluent 73.62 184.05 552.15 maize starch, EP/BP/NFMicrocrystalline Diluent/ 10.00 25.00 75.00 cellulose, EP disintegrantSodium starch Disintegrant 2.00 5.00 15.00 glycolate, EP Sodium laurylSurfactant 1.00 2.50 7.50 sulphate, EP/NF Extra- MicrocrystallineDiluent/ 10.00 25.00 75.00 granular cellulose, EP disintegrant Sodiumstarch Disintegrant 2.00 5.00 15.00 glycolate, EP Colloidal siliconeGlidant 0.30 0.75 2.25 dioxide, EP/NF Magnesium Lubricant 1.00 2.50 7.50stearate, EP/BP Total 100.000 250.00 750.00

Example 13

Compound of formula I Capsules 1.0 mg Typical Percentage Unit BatchMaterial Formula Dose Quantity (Chemical name) Function (% w/w) (mg) (g)Intra- Compound of Active 0.40 1.00 3.000 granular formula IPregelatinized Diluent 73.30 183.25 549.75 maize starch, EP/BP/NFMicrocrystalline Diluent/ 10.00 25.00 75.00 cellulose, EP disintegrantSodium starch Disintegrant 2.00 5.00 15.00 glycolate, EP Sodium laurylSurfactant 1.00 2.50 7.50 sulphate, EP/NF Extra- MicrocrystallineDiluent/ 10.00 25.00 75.00 granular cellulose, EP disintegrant Sodiumstarch Disintegrant 2.00 5.00 15.00 glycolate, EP Colloidal Glidant 0.300.75 2.25 silicone dioxide, EP/NF Magnesium Lubricant 1.00 2.50 7.50stearate, EP/BP Total 100.000 250.00 750.00

Example 14

Compound of formula I Capsules 10 mg Typical Percentage Unit BatchMaterial Formula Dose Quantity (Chemical name) Function (% w/w) (mg) (g)Intra- Compound of Active 4.00 10.00 30.00 granular formula IPregelatinized Diluent 69.70 174.25 522.75 maize starch, EP/BP/NFMicrocrystalline Diluent/ 10.00 25.00 75.00 cellulose, EP disintegrantSodium starch Disintegrant 2.00 5.00 15.00 glycolate, EP Sodium laurylSurfactant 1.00 2.50 7.50 sulphate, EP/NF Extra- MicrocrystallineDiluent/ 10.00 25.00 75.00 granular cellulose, EP disintegrant Sodiumstarch Disintegrant 2.00 5.00 15.00 glycolate, EP Colloidal Glidant 0.300.75 2.25 silicone dioxide, EP/NF Magnesium Lubricant 1.00 2.50 7.50stearate, EP/BP Total 100.000 250.00 750.00

Example 15

Compound of formula I Capsules 100 mg Typical Percentage Unit BatchMaterial Formula Dose Quantity (Chemical name) Function (% w/w) (mg) (g)Intra- Compound of Active 40.00 100.00 300.00 granular formula IPregelatinized Diluent 33.70 84.25 252.75 maize starch, EP/BP/NFMicrocrystalline Diluent/ 10.00 25.00 75.00 cellulose, EP disintegrantSodium starch Disintegrant 2.00 5.00 15.00 glycolate, EP Sodium laurylSurfactant 1.00 2.50 7.50 sulphate, EP/NF Extra- MicrocrystallineDiluent/ 10.00 25.00 75.00 granular cellulose, EP disintegrant Sodiumstarch Disintegrant 2.00 5.00 15.00 glycolate, EP Colloidal Glidant 0.300.75 2.25 silicone dioxide, EP/NF Magnesium Lubricant 1.00 2.50 7.50stearate, EP/BP Total 100.000 250.00 100.000

Examples 16-20

Batch size: 1 kg

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 14.2910.00 granular Pharmatose 200M 55.51 38.86 Avicel PH101 5.00 3.50Povidone K30 3.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.200.14 Water qs qs Extra- Avicel PH101 17.50 12.25 granular Sodium starchglycolate 2.00 1.40 Magnesium stearate 0.50 0.35 Total 100.00 70.00

The following parameters were used to make the 70 mg tablets of thecomposition given in the table above:

Example Press Mean hardness Mean thickness No. setting (Kp) (mm) 16 191.81 3.348 17 21 7.11 2.944 18 23 8.10 2.875 19 25 8.56 2.864 20 27 8.852.886

Examples 21-25

Batch size: 1 kg

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 0.43 0.30granular Pharmatose 200M 68.37 47.86 Avicel PH101 5.00 3.50 Povidone K304.00 2.80 Sodium starch glycolate 2.00 1.40 Tween 80V 0.20 0.14 Water qsqs Extra- Avicel PH101 17.50 12.25 granular Sodium starch glycolate 2.001.40 Magnesium stearate 0.50 0.35 Total 100.00 70.00

The following parameters were used to make the 70 mg tablets of thecomposition given in the table above (hardness and thickness parameterswere measured before possible coating):

Example Press Mean hardness Mean thickness No. setting (Kp) (mm) 21 191.52 3.339 22 21 5.77 3.048 23 23 6.32 2.989 24 25 6.88 3.059 25 27 6.953.006

Examples 26-30

Batch size: 1 kg

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 0.43 0.30granular Pharmatose 200M 68.37 47.86 Avicel PH101 5.00 3.50 Povidone K303.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.20 0.14 Water qsqs Extra- Avicel PH101 17.50 12.25 granular Sodium starch glycolate 2.001.40 Magnesium stearate 1.50 1.05 Total 100.00 70.00

The following parameters were used to make the 70 mg tablets of thecomposition given in the table above (hardness and thickness parameterswere measured before possible coating):

Example Press Mean hardness Mean thickness No. setting (Kp) (mm) 26 192.23 2.774 27 20 2.53 2.734 28 21 2.88 2.713 29 22 3.30 2.699 30 23 3.512.657

Example 31

Batch size: 500 g

250 mg tablets containing 1 mg of compound of formula I were preparedwith the composition indicated in the table hereafter, using parameterssimilar to those of Examples 16-30 above:

Compound of formula I tablets (250 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 0.40 1.00granular Starch 1500 74.60 186.50 Avicel PH101 10.00 25.00 Sodium starchglycolate 2.00 5.00 Water qs qs Extra- Avicel PH101 10.00 25.00 granularSodium starch glycolate 2.00 5.00 Magnesium stearate 1.00 2.50 Total100.00 250.00

Example 32

Batch size: 500 g

70 mg tablets containing 1 mg of compound of formula I and having a meanhardness of 4 kP were prepared with the composition indicated in thetable below, using parameters similar to those of Examples 16-30 above:

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 1.43 1.00granular 200M lactose 70.86 49.60 Maize starch 20.00 14.00 Povidone K303.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.14 0.10 Water qsqs Extra- Sodium starch glycolate 2.00 1.40 granular Magnesium stearate0.57 0.40 Total 100.00 70.00

Example 33

Batch size: 500 g

70 mg tablets containing 1 mg of compound of formula I were preparedwith the composition indicated in the table below, using parameterssimilar to those of Examples 16-30 above:

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 1.40 0.98granular 200M lactose 62.50 43.75 Avicel PH101 5.00 3.50 Povidone K303.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.10 0.07 Tartaricacid 6.00 4.20 Water qs qs Extra- Avicel PH101 17.50 12.25 granularSodium starch glycolate 2.00 1.40 Magnesium stearate 0.50 0.35 Total100.00 70.00

Example 34

Batch size: 500 g

Percentage Formula Unit Dose Materials (% w/w) (mg) Compound of formulaI 1.40 0.98 Anhydrous lactose 71.60 50.12 Avicel PH112 22.50 15.80Sodium starch glycolate 4.00 2.80 Magnesium stearate 0.50 0.40 Total100.0 70.00

Example 35

Batch size: 500 g

Percentage Formula Unit Dose Materials (% w/w) (mg) Compound of formulaI 1.40 0.98 Mannitol (SD200) 71.60 50.12 Avicel PH112 22.50 15.80 Sodiumstarch glycolate 4.00 2.80 Magnesium stearate 0.50 0.40 Total 100.070.00

Example 36

70 mg tablets containing 10 mg of compound of formula I made as inExample 17 above were coated using the general tablet coatingmethodology with Opadry® AMB mentioned above with the followingparticular coating parameters (NB: the quantities mentioned for thesolids and coating solution are such to allow the coating of a batch of7300 g of uncoated tablets):

% w/w target for tablet coating  4% Weight of solids required to coat(g) 292 % w/w of coating solution 20% Weight of coating solutionrequired (g) 1460

Example 37

70 mg tablets containing 10 mg of compound of formula I made as inExample 17 above were coated using the general tablet coatingmethodology with Opadry® AMB mentioned above with the followingparticular coating parameters (NB: the quantities mentioned for thesolids and coating solution are such to allow the coating of a batch of7300 g of uncoated tablets):

% w/w target for tablet coating  6% Weight of solids required to coat(g) 438 % w/w of coating solution 20% Weight of coating solutionrequired (g) 2190

Example 38

70 mg tablets containing 10 mg of compound of formula I made as inExample 17 above (having a diameter of 5 mm and a height of 3.1 mm) werecoated using the general tablet coating methodology with EUDRAGIT® E POmentioned above. The uncoated tablet batch size was 500 g. The followingquantities of EUDRAGIT® E PO, sodium lauryl sulphate, stearic acid,magnesium stearate and water were used:

EUDRAGIT ® E PO (g) 26.3 Sodium lauryl sulphate (g) 2.6 Stearic acid (g)3.9 Magnesium stearate (g) 9.2 Water 238.4

Example 39

70 mg tablets containing 0.3 mg of compound of formula I made as inExample 28 above (having a diameter of 5 mm and a height of 2.9 mm) werecoated using the general tablet coating methodology with EUDRAGIT® E POmentioned above. The uncoated tablet batch size was 600 g. The followingquantities of EUDRAGIT® E PO, sodium lauryl sulphate, stearic acid andmagnesium stearate were used:

EUDRAGIT ® E PO (g) 92.0 Sodium lauryl sulphate (g) 9.2 Stearic acid (g)13.8 Magnesium stearate (g) 32.2 Water 834.3

Example 40

Batch size: 1.5 kg

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 14.2910.00 granular Pharmatose 200M 55.51 38.86 Avicel PH101 5.00 3.50Povidone K30 3.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.200.14 Water qs qs Extra- Avicel PH101 17.50 12.25 granular Sodium starchglycolate 2.00 1.40 Magnesium stearate 0.50 0.35 Total 100.00 70.00

Example 41

Batch size: 45 kg

Compound of formula I tablets (70 mg) Material Percentage Formula UnitDose (Chemical name) (% w/w) (mg) Intra- Compound of formula I 14.2910.00 granular Pharmatose 200M 55.51 38.86 Avicel PH101 5.00 3.50Povidone K30 3.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.200.14 Water qs qs Extra- Avicel PH101 17.50 12.25 granular Sodium starchglycolate 2.00 1.40 Magnesium stearate 0.50 0.35 Total 100.00 70.00

Example 42

70 mg tablets containing 10 mg of compound of formula I made as inExample 41 above were coated using the general tablet coatingmethodology with Opadry® AMB mentioned above with the followingparticular coating parameters (NB: the quantities mentioned for thesolids and coating solution are such to allow the coating of a batch of7300 g of uncoated tablets):

% w/w target for tablet coating  4% Weight of solids required to coat(g) 292 % w/w of coating solution 20% Weight of coating solutionrequired (g) 1460

The mean hardness of the tablets thus obtained was 7.7 Kp.

Example 43

Batch size: 45 kg

Compound of formula I tablets (70 mg) MATERIAL Percentage Formula UnitDose (CHEMICAL NAME) (% w/w) (mg) Intra- Compound of formula I 4.29 3.00granular Pharmatose 200M 65.51 45.86 Avicel PH101 5.00 3.50 Povidone K303.00 2.10 Sodium starch glycolate 2.00 1.40 Tween 80V 0.20 0.14 Water qsqs Extra- Avicel PH101 17.50 12.25 granular Sodium starch glycolate 2.001.40 Magnesium stearate 0.50 0.35 Total 100.00 70.00

Example 44

70 mg tablets containing 3 mg of compound of formula I made as inExample 43 above were coated using the general tablet coatingmethodology with Opadry® AMB mentioned above with the followingparticular coating parameters (NB: the quantities mentioned for thesolids and coating solution are such to allow the coating of a batch of7300 g of uncoated tablets):

% w/w target for tablet coating  4% Weight of solids required to coat(g) 292 % w/w of coating solution 20% Weight of coating solutionrequired (g) 1460

The mean hardness of the tablets thus obtained was 7.7 Kp.

Experimental Study of the Pharmaceutical Compositions of the Invention:Stability Test:

The quantity of substances related to the compound of formula I (i.e.products coming from the degradation of the compound of formula I) thatare present after a certain time of storage at 40° C. with 75% relativehumidity can be determined by HPLC for the pharmaceutical compositionsof the Reference Examples and Examples above.

The experimental results obtained for the compositions of ReferenceExamples RE1 to RE4 can be summarized by the following table (thecompound of formula I used in Reference Examples RE1 to RE4 had always apurity greater than 99.5%):

Reference Substances related to the compound of formula I found ExampleNo. after 15 weeks storage at 40° C. with 75% relative humidity RE15.76% RE2 6.20% RE3 8.48% RE4 5.14%

The experimental results obtained for the composition of Example 40 canbe summarized by the following table (the compound of formula I used inExample 40 had a purity greater than 99.5%):

Substances related to the compound of formula I found Time of storagewhen stored at 40° C. with 75% relative humidity 1 month 0.07% 2 months0.10% 3 months 0.14%

The experimental results obtained for the composition of Example 42 canbe summarized by the following table (the compound of formula I used inExample 42 had a purity greater than 99.5%):

Substances related to the compound of formula I found Time of storagewhen stored at 40° C. with 75% relative humidity 3 months 0.07% 6 months0.10%

Finally, the experimental results obtained for the composition ofExample 44 can be summarized by the following table (the compound offormula I used in Example 44 had a purity greater than 99.5%):

Substances related to the compound of formula I found Time of storagewhen stored at 40° C. with 75% relative humidity 3 months 0.08% 6 months0.23%

Dissolution Test: Apparatus

The following materials are used for the dissolution test:

-   -   Type USP apparatus 2: SOTAX AT7 Dissolution Test station or        equivalent, 6×1000 ml dissolution vessels and 6 paddles.    -   HPLC system Agilent 1100 with data acquisition (Chemstation        Plus).    -   Analysis Balance METTLER AX 205 DR    -   Milli-Q gradient A10 MILLIPORE, F1KN13093 H

Working Conditions of the Apparatus

The following conditions are used for the dissolution test:

-   -   Dissolution apparatus:        -   Temperature: 37.0±0.5° C.        -   Speed: 50±2 rpm        -   Volume: 900 ml        -   Dissolution medium: Buffer pH=6.8 with 0.05% Tween 80        -   Sampling volume: 12 ml without medium replacement        -   Sampling time point(s): profile at 5, 10, 15, 30, 45, 60 min    -   HPLC parameters:        -   Stationary phase: EC 250/3 Nucleodur C18 gravity 3 μm (cat.            No. 7600820.30)        -   Column: 250 mm×3.00 mm 3 μm (Macherey-Nagel)        -   Mobile phase: Isocratic        -   Injected volume: 10 μl        -   Column temperature: 25° C.        -   Auto sampler temperature: 25° C.        -   Flow rate: 0.5 ml/min        -   Pressure: 149 bar        -   Detection wavelength: 260 nm        -   Chromatogram time: 10 min        -   Mobile phase: Mix well 850 ml acetonitrile, 150 ml water and            5 ml trifluoroacetic acid. Degas before use.

Protocol

10 l of the dissolution medium are prepared as follows: 79.85 g ofNaH₂PO₄.2H₂O, 69.55 g of Na₂HPO₄ and 5 g of Tween 80 are diluted withwater to a total volume of 10 l.

A reference standard solution of compound of formula I is prepared induplicate. One of the reference standard solutions will be used as theworking reference standard solution, and the other standard solutionwill be used as a control reference standard solution. A referencestandard solution of compound of formula I is obtained as follows:

55 mg of compound of formula I are weighed in a 250 ml volumetric flaskand 4 ml acetonitrile are added. The mixture is sonicated for 5 minutes.After complete dissolution of the compound of formula I, dissolutionmedium is added to complete to 250 ml. 10.0 ml of this solution aretaken by pipette into a 200 ml volumetric flask, dissolution medium isadded to complete to 250 ml. The concentration of compound of formula Iin the reference standard solution is thus 11 μg/ml.

The dissolution sample solution is prepared as follows:

900 ml of dissolution medium are transferred into each vessel of thedissolution apparatus. The dissolution medium is allowed to equilibratefor at least 30 min in the dissolution batch at 37° C.±0.5° C. A 10 mgtablet of compound of formula I is dropped into each vessel. 12 ml ofthe sample solution are withdrawn from each vessel at 5, 10, 15, 30, 45and 60 min. No medium replacement is required. The sample solution isfiltered without delay through a Gelman 1 μm glass fibre acrodisksyringe filter into an HPLC vial and cooled to room temperature.

The following injection sequence is used for carrying out the HPLCanalysis:

-   -   the dissolution medium is injected once;    -   the working reference standard solution is injected 6 times        consecutively;    -   the control reference standard solution is injected twice;    -   each sample solution is injected once.

After the six samples injections, the working reference standardsolution is re-injected to ensure that the system drift is within thelimit (2.0%).

The following criteria must be met:

-   -   The working reference standard solution is consecutively        injected six times. The % RSD from the response factors (i.e.        the concentration of the reference solution divided by the peak        area of the reference solution) should be ≤2.0%. The overall RSD        of response factor of compound of formula I in the working        reference standard solution injected throughout the run should        be ≤2.0%.    -   The relative difference between the mean response factor of 6        injections of the working reference standard solution and the        mean of 2 injections of the control reference standard solution        should be ≤1.5%.

The results can be calculated using the following formulae:

${D(\%)} = {\frac{{C_{n}V_{n}} + {\sum\limits_{i = 1}^{n - 1}\; {C_{i}V_{r}}}}{T} \times 100}$V_(n) = V − V_(r) (n − 1)$C = {\frac{A_{spl}}{A_{std}} \times c_{std}}$$C_{std} = {\frac{W_{std}}{DF_{std}} \times \frac{P_{std}}{100}}$N Sampling time (min) $\sum\limits_{i = 1}^{n - 1}{C_{i}V_{r}}$ 1 5 02 10 C₁ V_(r) 3 15 (C₁ + C₂)V_(r) 4 30 (C₁ + C₂ + C₃)V_(r) 5 45 (C₁ +C₂ + C₃ + C₄)V_(r) 6 60 (C₁ + C₂ + C₃ + C₄ + C₅)V_(r) etc.wherein

-   D(%)=compound of formula I dissolved based on labeled quantity-   C_(n)=concentration of compound of formula I for the n^(th)    injection, in mg/ml-   V=initial volume of dissolution medium, in ml=900-   V_(r)=volume of dissolution medium removed for each injection, in    ml=12-   V_(n)=actual volume of dissolution medium, in ml, for the n^(th)    injection-   T=labeled quantity of compound of formula I per tablet=10 mg-   n=n^(th) sampling-   A_(spl)=peak area of compound of formula I obtained from the sample    solution-   A_(std)=peak area of compound of formula I obtained from the working    reference standard solution-   C_(std) concentration in mg/ml, of compound of formula I in the    working reference standard solution-   W_(std) weight of compound of formula I in the working reference    standard solution, in mg-   P_(std)=potency of compound of formula I reference substance in %-   DF_(std)=dilution factor of the standard solution, in ml=5,000

Results for Pharmaceutical Compositions According to the Invention:

The compositions of Examples 16-20, when tested using the protocolexplained, show the dissolution profile shown in FIG. 1 (wherein thepercentage dissolution (Y-axis) is represented in function of the timein min (X-axis)).

The dissolution profiles of the tablets of this invention can also betested using the method described above after a certain time of storageat 40° C. with 75% relative humidity.

Accordingly, the dissolution profiles obtained for the tablets ofExample 40 are as follows.

Time of storage at % of compound of formula I dissolved after 40° C.with 75% (ranges of values found) relative humidity 5 minutes 10 minutes15 minutes 30 minutes 45 minutes 60 minutes None 45 (36-63) 91 (88-96)102 (98-105)  110 (105-114)  107 (102-112)  105 (101-109) 1 month 41(35-48) 87 (84-91) 103 (95-115) 114 (98-133) 112 (98-129) 111 (97-124) 2months 40 (36-43) 62 (58-65) 73 (68-80) 86 (81-92) 90 (86-96) 92(86-100) 3 months 51 (49-52) 64 (56-68) 72 (70-75) 82 (80-86) 86 (84-88)87 (82-90) 

Furthermore, the results obtained for the tablets of Example 42 can besummarized as follows:

Time of storage at % of compound of formula I dissolved after 40° C.with 75% (ranges of values found) relative humidity 5 minutes 10 minutes15 minutes 30 minutes 45 minutes 60 minutes None 46 (41-52) 76 (74-79)86 (81-91) 94 (89-98) 96 (89-100) 96 (91-100) 3 months 56 (47-66) 83(82-86) 89 (83-92) 94 (90-99) 96 (91-99)  96 (91-101) 6 months 61(57-65)83 (79-88) 88 (83-94)  96 (92-101) 96 (91-100) 97 (92-101)

Moreover, the results obtained for the tablets of Example 44 can besummarized as follows:

Time of storage at % of compound of formula I dissolved after 40° C.with 75% (ranges of values found) relative humidity 5 minutes 10 minutes15 minutes 30 minutes 45 minutes 60 minutes None 45 (42-49) 81 (78-86)90 (87-94)  96 (93-100)  98 (95-101)  98 (96-101) 3 months 39 (35-43) 84(82-88) 90 (88-92) 94 (91-96) 94 (92-97) 94 (91-97) 6 months 39 (34-43)79 (77-83) 86 (84-89) 91 (87-94) 91 (88-93) 91 (88-93)

1-9. (canceled)
 10. A pharmaceutical composition comprising: a) thecompound of the formula I as drawn below

or a pharmaceutically acceptable salt, solvate, hydrate or morphologicalform thereof, in a total amount of 1 to 50% in weight based on the totalweight of the pharmaceutical composition, b) filler, in an amount of 10to 95% in weight based on the total weight of the pharmaceuticalcomposition, c) disintegrant, in an amount of 1 to 20% in weight basedon the total weight of the pharmaceutical composition, d) surfactant, inan amount from 0.1 to 1% in weight based on the total weight of thepharmaceutical composition, wherein the surfactant comprises apolysorbate, e) lubricant, in an amount from 0.05 to 10% in weight basedon the total weight of the pharmaceutical composition, and f) glidant,in an amount from 0.1 to 5% in weight based on the total weight of thepharmaceutical composition.
 11. The pharmaceutical composition of claim10, wherein the filler comprises one or more from lactose, maize starch,pregelatinized starch, dibasic calcium phosphate dihydrate(CaHPO₄.2H₂O), microcrystalline cellulose, maltodextrin and mannitol.12. The pharmaceutical composition of claim 11, wherein the fillercomprises lactose.
 13. The pharmaceutical composition of claim 11,wherein the filler comprises microcrystalline cellulose.
 14. Thepharmaceutical composition of claim 11, wherein the filler compriseslactose and microcrystalline cellulose.
 15. The pharmaceuticalcomposition of claim 11, wherein the filler comprises maize starch. 16.The pharmaceutical composition of claim 11, wherein the filler comprisespregelatinized starch.
 17. The pharmaceutical composition of claim 11,wherein the filler comprises dibasic calcium phosphate dihydrate(CaHPO₄.2H₂O).
 18. The pharmaceutical composition of claim 11, whereinthe filler comprises mannitol.
 19. The pharmaceutical composition ofclaim 10, wherein the disintegrant comprises one or more fromcroscarmellose sodium, sodium starch glycolate, calciumcarboxymethylcellulose, sodium carboxymethylcellulose, cross-linkedpolyvinylpyrrolidone, polyvinylpyrrolidone, alginic acid, sodiumalginate, pregelatinized starch, guar gum, clays and ion exchangeresins.
 20. The pharmaceutical composition of claim 19, wherein thedisintegrant comprises croscarmellose sodium.
 21. The pharmaceuticalcomposition of claim 19, wherein the disintegrant comprises sodiumstarch glycolate.
 22. The pharmaceutical composition of claim 19,wherein the disintegrant comprises cross-linked polyvinylpyrrolidone.23. The pharmaceutical composition of claim 19, wherein the disintegrantcomprises polyvinylpyrrolidone.
 24. The pharmaceutical composition ofclaim 19, wherein the disintegrant comprises pregelatinized starch. 25.The pharmaceutical composition of claim 10, wherein the polysorbate ispolysorbate
 80. 26. The pharmaceutical composition of claim 10, whereinthe lubricant comprises one or more from magnesium stearate, aluminiumstearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc,sodium benzoate, a glyceryl mono fatty acid, glyceryl dibehenate,glyceryl palmito-stearic ester, polyethylene glycol, hydrogenated cottonseed oil, castor seed oil and sucrose esters.
 27. The pharmaceuticalcomposition of claim 26, wherein the lubricant comprises magnesiumstearate.
 28. The pharmaceutical composition of claim 26, wherein thelubricant comprises aluminium stearate.
 29. The pharmaceuticalcomposition of claim 26, wherein the lubricant comprises calciumstearate.
 30. The pharmaceutical composition of claim 26, wherein thelubricant comprises stearic acid.
 31. The pharmaceutical composition ofclaim 10, wherein the glidant comprises one or more from silica;colloidal silicon dioxide, magnesium trisilicate, powdered cellulose,starch and talc.
 32. The pharmaceutical composition of claim 31, whereinthe glidant comprises colloidal silicon dioxide.
 33. The pharmaceuticalcomposition of claim 31, wherein the glidant comprises starch.
 34. Thepharmaceutical composition of claim 10, which is in the form of atablet.
 35. The pharmaceutical composition of claim 11, which is in theform of a tablet.
 36. The pharmaceutical composition of claim 19, whichis in the form of a tablet.
 37. The pharmaceutical composition of claim25, which is in the form of a tablet.
 38. The pharmaceutical compositionof claim 26, which is in the form of a tablet.
 39. The pharmaceuticalcomposition of claim 31, which is in the form of a tablet.
 40. A methodof treating pulmonary arterial hypertension comprising theadministration of a pharmaceutical composition according to claim 10 toa patient in need thereof.
 41. A method of treating pulmonary arterialhypertension comprising the administration of a pharmaceuticalcomposition according to claim 34 to a patient in need thereof.